Genetic information flows from DNA to macromolecular structures - the dominant force in the molecular organization of life. However, virtually all cell surface and secreted proteins in metazoans are modified by the addition of complex carbohydrates in the ER/Golgi secretory pathway. We find that metabolite availability to the Golgi N-glycosylation pathway exerts autonomous control over the assembly of macromolecular complexes on the cell surface, and in this capacity, acts upstream of signaling and gene expression to influence cell growth, differentiation and disease states. The branching and number of N-glycans per protein molecule cooperate to regulate binding to galectins and thereby the distribution, clustering and endocytosis of surface glycoproteins in a predictable manner. Genetic disruption of N-glycosylation promotes T cell hyper-activity and autoimmune disease in mice by enhancing T cell receptor clustering/signaling and reducing surface retention of the growth inhibitor CTLA-4. In humans, a haplotype of MGAT1 that reduces N-glycan branching in glycoproteins by ~20% synergistically interacts with an allele of CTLA-4 that reduces N-glycan number by ~50%, increasing the risk of Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) by ~2 fold. The two variants are expected to independently reduce CTLA-4 affinity for galectins and indeed, they act cooperatively to limit surface CTLA-4 surface levels. Disease promotion is observed only in subjects who harbor both variants, and appears to be titrated by the number of copies of the defective CTLA-4 allele. Metabolic supplementation to the Golgi inhibits T cell function and autoimmunity in mice and rescues the N-glycosylation defects in T cell growth and CTLA-4 surface retention associated with MS and RA. Our data suggests synergism in the etiology of human autoimmunity between polymorphisms that conditionally suppress Golgi GlcNAc branching and N-X-S/T site usage in CTLA-4, and provides a therapeutic strategy and molecular mechanism for environmental and genetic interactions. To extend these results in humans we propose the following aims. Specific Aim 1 will identify genetic variants that alter N-glycan branching. Specific Aim 2 will investigate the regulation of N-glycan branching by MS associated alleles and their interaction with variants identified in Aim 1. Specific Aim 3 will investigate for cooperative interactions between variants that alter N-glycan branching and CTLA-4 Ala17 and related alleles. Specific Aim 4 will examine for genetic interaction of variants from Specific Aim's 1-3 in Multiple Sclerosis and Type 1 Diabetes co-horts.